Inorganic Arsenic is a toxic compound with significant public health impact. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL), and arsenic has been found in at least 781 of these sites. Arsenic is also a by-product of coal combustion, as well as a naturally occurring water contaminant in many regions of the world, including the USA, Exposure may occur by a variety of pathways including inhalation of dusts in air, ingestion of contaminated soil or water, or through the food chain. Arsenic has been associated with a number of adverse health effects. However, the precise relation of arsenic to pregnancy outcomes has not been established. Thus, we wish to extend the previous work we conducted in Taiwan and Bangladesh to an assessment of birth outcomes in a prospective, repeated measures study of expectant mothers and their newborns in Bangladesh. Currently, an estimated 133 million people in Bangladesh are at risk of disease from drinking arsenic-contaminated drinking water. The proposed studies will evaluate standard birth outcomes at exposure levels that are relevant not only to the U.S. population, but also globally. The proposed studies will assess this risk in a population with a wide range of exposure, from low to high. Together, these data will add substantially to the existing risk assessment information by elucidating birth outcomes after arsenic exposure;the role of methylated forms of arsenic in the urine as biomarkers of exposure and risk;and an evaluation of a new potential marker of adverse outcome (proteomic profiles), as well as the influence of candidate genetic susceptibility traits as risk modifiers. This project is relevant to the overall strategic plan of the NIEHS in several ways. Firstly, we will examine a range of health effects of a significant environmental toxicant, arsenic. Secondly, we will define human biomarkers of exposure, early effects, and genetic susceptibility to arsenic exposure. Thirdly, we will examine exposure-response relationships for arsenic-induced birth outcomes. Fourthly, we will incorporate new, sensitive toxicogenomic technology (proteomics) to assess potentially novel biomarkers of exposure and effect in a molecular epidemiologic setting. Lastly, the study is international, sited in the developing world. The proposed human studies will fill important research gaps in our knowledge of arsenic toxicity and inform clinical and public health interventions.